Elderly gynaecological cancer patients at risk for poor end of life care: a population-based study from the Swedish Register of Palliative Care.

Introduction: Poorer end-of-life (EOL) care for elderly cancer patients has been reported. We assessed the impact of age on 13 indicators for the quality of EOL care as well as adherence to 6 national quality indicators in gynaecological cancer patients.Methods: Age-dependent differences in 13 palliative care quality indicators were studied in gynaecological cancer patients registered in the population-based Swedish Register of Palliative Care. Association between the patient's age and each quality indicator was analyzed by logistic regression, adjusted for place of death where appropriate. Adherence to six national quality indicators determined by the Swedish National Board of Health and Welfare was estimated in all patients.Results: We included 3940 patients with the following age distribution: 1.6% were 18-39 years of age, 12.3% 40-59 years, 37.2% 60-74 years, 28.9% 75-84 years and 20% were ≥85 years. Age-dependent differences in implementation rate were present for some of the 13 quality indicators. Compared to elderly cancer patients, younger patients were more likely to be cared for by a specialized palliative care service, more often informed about imminent death as well as assessed for pain. For most national quality indicators, the goal level was not met. Only for the 'on demand prescription for pain', the goal level was reached.Conclusions: EOL care did not meet national quality indicators in this population-based data from Sweden, in particular in the elderly population. Elderly gynaecological cancer patients are at high risk of poorer EOL care without the involvement of specialized palliative care services. Palliative care services need to be implemented across all institutions of EOL care to ensure good and equal care.

Conservative management of endometrial cancer: a survey amongst European clinicians.

OBJECTIVE: To investigate differences and similarities in the clinical approach of young clinicians managing women with endometrial cancer (EC) conservatively. METHODS: A web-based survey was carried out. A platform of the European Network of Young Gynaecological Oncologists (ENYGO) database was used. A 38-item multiple-choice questionnaire was used to evaluate current practice in fertility-sparing management of EC. The survey covered investigations, treatment options, follow-up and management of recurrence and future family planning. Descriptive statistics were used. RESULTS: Overall, 116 out of 650 (17.84%) ENYGO members responded to the survey. In 92 (79.3%) centres, the caseload of early stage EC treated conservatively was less than 10 per year. One hundred and seven responders (93.8%) believe that treatment with progestins could be offered in grade 1 EC without myometrial invasion, but a minority would recommend it even for grade 2 tumours with no myometrial invasion or grade 1 with superficial invasion. The diagnostic tool for establishing grade of tumour was hysteroscopy with dilatation and curettage in 64 (55%) centres. Medroxyprogesterone acetate represents the most commonly prescribed progestogen (55, 47.4%). In 78 (67.2%) centres, a repeat endometrial biopsy was offered after 3 months of treatment commencement. Recurrences are treated mostly with hysterectomy (81, 69.9%) with only a small number of responders recommending to repeat progestin treatment. Lynch syndrome is a contraindication for conservative management in half of the responders (57, 49.1%). Most clinicians agree that patients should be referred promptly for assisted reproductive techniques once complete response has been achieved (68, 58.6%). CONCLUSIONS: Our study shows that conservative management is increasingly offered to women affected by early stage EC wishing to preserve their fertility. Further studies and joint registries are required to evaluate safety and effectiveness of this approach in this probably growing number of patients.

Human papillomavirus, p16(INK4A), and Ki-67 in relation to clinicopathological variables and survival in primary carcinoma of the vagina.

BACKGROUND: This study aimed to determine human papillomavirus (HPV) status and to investigate p16(INK4A) and Ki-67 expression and their correlation with clinical parameters and survival in women with primary carcinoma of the vagina (PCV). METHODS: The presence of HPV DNA was evaluated by PCR. Genotyping was performed by Luminex in 68 short-term (2 years) and long-term (8 years) PCV survivors. p16(INK4A) and Ki-67 expression was evaluated by immunohistochemistry. RESULTS: Human papillomavirus DNA was detected in 43% of patients, the majority (63%) of whom were HPV16 positive. High p16(INK4A) expression was significantly correlated with low histopathological grade (P=0.004), HPV positivity (P=0.032), and long-term survival (P=0.045). High Ki-67 expression was negatively correlated with histopathological grade (P<0.001) and tumour size (P=0.047). There was an association between HPV positivity and low histopathological grade, but not between HPV positivity and survival. CONCLUSION: High p16(INK4A) expression was associated with long-term survival, but the only independent predictors for survival were tumour size and histopathological grade. Our results indicate that p16(INK4A) and Ki-67 expression might be useful in tumour grading, and that it might be possible to use p16(INK4A) expression as a marker for HPV positivity, but this has to be further elucidated.

Expression of LRIG1 is associated with good prognosis and human papillomavirus status in oropharyngeal cancer.

BACKGROUND: The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer has increased rapidly during the past decades. HPV is typically associated with a favourable outcome; however, a need exists for new and more effective prognostic and predictive markers for this disease. Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a tumour suppressor protein that belongs to the LRIG family. LRIG1 expression has prognostic significance in various human cancers, including cervical cancer, where HPV is a key aetiological agent. METHODS: The prognostic value of LRIG1 and LRIG2 immunoreactivity was investigated in tumour specimens from a Swedish cohort of patients with tonsillar and base of tongue oropharyngeal cancers, including 278 patients. RESULTS: LRIG1 immunoreactivity correlated with disease-free survival and overall survival in univariate and multivariate analyses. Notably, patients with HPV-positive tumours with high LRIG1 staining intensity or a high percentage of LRIG1-positive cells showed a very good prognosis. Furthermore, LRIG1 expression correlated with HPV status, whereas LRIG2 expression inversely correlated with HPV status. CONCLUSIONS: Taken together, the results suggest that LRIG1 immunoreactivity could be a clinically important prognostic marker in HPV-associated oropharyngeal cancer.

Pegylated liposomal doxorubicin plus carboplatin in patients with metastatic breast cancer: a phase II study.

BACKGROUND: We determined the objective response rates produced by pegylated liposomal doxorubicin (PLD) plus carboplatin with/without trastuzumab (Herceptin). PATIENTS AND METHODS: Patients with measurable disease were stratified by taxane treatment history and human epidermal growth factor receptor-2 status. TREATMENT: PLD 30 mg/m(2) followed by carboplatin, day 1 of each 28-day cycle; human epidermal growth factor receptor-2 (HER2)-positive patients also received trastuzumab. RESULTS: Arm 1 received PLD plus carboplatin (N = 41 arm 1a, taxane naive; N = 42 arm 1b, taxane pretreated); Arm 2 patients received PLD plus carboplatin + Herceptin (N = 46). Overall response rates: 31%, 31%, and 56%, respectively. Median overall survival durations were not reached in arm 1a and were 13 and 33 months for arms 1b and 2. Median progression-free survival: 8, 5, 10 months, respectively. Grades 3-4 treatment-related toxic effects for arms 1a, 1b, 2, respectively, were neutropenia 22%, 31%, 35%; thrombocytopenia 34%, 26%, 17%; and fatigue 2%, 14%, 13%. CONCLUSIONS: PLD plus carboplatin has moderate antitumor activity and excellent tolerability. Herceptin and PLD plus carboplatin in HER2-positive patients have antitumor activity without significant cardiac toxicity. Toxicity results suggest that PLD can be combined with Herceptin with minimal cardiac toxicity.

Disease Extent ≥4 cm Is a Prognostic Marker of Local Recurrence in T1-2 Breast Cancer.

Despite improvements of the therapy for breast cancer, a proportion of the patients still get local recurrence. The status of the surgical margins is the most often used parameter for decision regarding additional treatment. However, a negative margin is not a guarantee that there is not residual cancer left in the breast; additional parameters are needed to better predict the risk of local recurrence. The disease extent was evaluated in the surgical specimen from 313 women after breast-conserving therapy using large-section histology and was correlated to the incidence of local recurrence. A disease extent ≥4 cm was shown to be an independent marker for local recurrence; the cumulative 10-year local relapse rate for the group with a disease extent ≥4 cm was 20.5%, and for the rest 6.7%. We conclude that disease extent ≥4 cm seems to be an important factor when evaluating the risk for local recurrence.

Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis.

White matter (WM) lesions are the classic pathological hallmarks of multiple sclerosis (MS). However, MRI-based WM lesion load shows relatively poor correlation with functional outcome, resulting in the "clinico-radiological paradox" of MS. Unlike lesion based measures, volumetric MRI assessment of brain atrophy shows a strong correlation with functional outcome, and the presence of early atrophy predicts a worse disease course. While extensive literature exists describing MRI characteristics of atrophy in MS, the exact pathogenesis and the substrate of atrophy-gray vs. WM loss, axonal/neuronal damage vs. demyelination, or a combination of the above-remain unclear. Animal models of atrophy would allow for detailed investigations of the pathomechanism, and would contribute to an enhanced understanding of structural-functional connections in this complex disease. We now report that in the Theiler's Murine Encephalitis Virus (TMEV) model of MS in SJL/J mice, significant brain atrophy accompanies the development of the progressive MS-like disease. We conducted volumetric MRI studies in 8 cases and 4 age, gender- and strain-matched control mice. While in controls we did not detect any brain atrophy, significant atrophy developed as early as 3 months into the disease course, and reached its peak by 6 months, resulting in ventricular enlargement by 118% (p=0.00003). A strong correlation (r=-0.88) between atrophy and disability, as assessed by rotarod assay, was also demonstrated. We earlier reported another neurodegenerative feature in this model, the presence of deep gray matter T2 hypointensity in thalamic nuclei. Future studies utilizing this model will allow us to investigate key components of MRI detectable neurodegenerative feature development, their tissue correlations and associations with functional outcome measures. These studies are expected to pave the way to a better understanding of the substrate of disability in MS models.

Muscle hypertrophy following 5-week resistance training using a non-gravity-dependent exercise system.

AIM: The efficacy of a mechanical, gravity-independent resistance exercise (RE) system to induce strength gains and muscle hypertrophy was validated. Designed for space crew in orbit, this technique offers resistance during coupled concentric and eccentric actions by utilizing the inertia of a rotating flywheel(s), set in motion by the trainee. METHODS: Ten middle-aged (30-53 years) men and women performed four sets of seven maximal, unilateral (left limb) knee extensions two or three times weekly for 5 weeks. Knee extensor force and electromyographic (EMG) activity of the three superficial quadriceps muscles were measured before and after this intervention. In addition, with the use of magnetic resonance imaging (MRI), volume of individual knee extensor and ankle plantar flexor muscles was assessed. RESULTS: Over the 12 training sessions, the average concentric (CON) and eccentric (ECC) force generated during exercise increased by 11% (P < 0.05). Likewise, maximal isometric strength (maximal voluntary contraction, MVC) at 90 and 120 degrees knee angle increased by (P < 0.05) 11 and 12% respectively, after training. Neither individual quadriceps muscle showed a change (P > 0.05) in maximal integrated EMG (iEMG) activity. Quadriceps muscle volume increased by 6.1% (P < 0.05). Although the magnitude of response varied, all individual quadriceps muscles showed increased (P < 0.05) volume after training. As expected, ankle plantar flexor volume of the trained limb was unchanged (P > 0.05). Likewise, MVC, CON and ECC force, iEMG and knee extensor and plantar flexor muscle volume were unaltered (P > 0.05) in the right, non-trained limb. CONCLUSION: The results of this study show that the present RE regimen produces marked muscle hypertrophy and important increases in maximal voluntary strength and appears equally effective as RE paradigms using gravity-dependent weights, in this regard.

Amygdala lesions block conditioned enhancement of the early component of the rat eyeblink reflex.

A tone conditioned stimulus (CS) previously paired with a grid shock unconditioned stimulus (US) can greatly enhance the early electromyographic (EMG) component (R1) of the rat eyeblink reflex. The hypothesis that the central nucleus of the amygdala (ACe) is an essential part of the circuitry mediating conditioned R1 enhancement was tested. After bilateral ACe lesions (L) or a sham operation (S), rats received paired presentations of the CS and US (P) or explicitly unpaired CS and US presentations (U), resulting in 4 groups: P/S, P/L, U/S, and U/L. ACe lesions completely prevented conditioned R1 enhancement, which was only exhibited in Group P/S. In the latter group, the "preextinction" conditioned enhancement effect was roughly a 2-fold increase in the R1 magnitude. Circuit-level mechanisms are discussed, and some advantages of the eyeblink EMG response in this general conditioning paradigm are considered.

Muscle-specific atrophy of the quadriceps femoris with aging.

We examined the size of the four muscles of the quadriceps femoris in young and old men and women to assess whether the vastus lateralis is an appropriate surrogate for the quadriceps femoris in human studies of aging skeletal muscle. Ten young (24 +/- 2 yr) and ten old (79 +/- 7 yr) sedentary individuals underwent magnetic resonance imaging of the quadriceps femoris after 60 min of supine rest. Volume (cm3) and average cross-sectional area (CSA, cm2) of the rectus femoris (RF), vastus lateralis (VL), vastus intermedius (VI), vastus medialis (VM), and the total quadriceps femoris were decreased (P < 0.05) in older compared with younger women and men. However, percentage of the total quadriceps femoris taken up by each muscle was similar (P > 0.05) between young and old (RF: 10 +/- 0.3 vs. 11 +/- 0.4; VL: 33 +/- 1 vs. 33 +/- 1; VI: 31 +/- 1 vs. 31 +/- 0.4; VM: 26 +/- 1 vs. 25 +/- 1%). These results suggest that each of the four muscles of the quadriceps femoris atrophy similarly in aging men and women. Our data support the use of vastus lateralis tissue to represent the quadriceps femoris muscle in aging research.

Contribution of trifluoperazine metabolites to the in vivo (19)F NMR spectrum of rat brain.

Fluorine-19 NMR spectra were acquired from extracts of tissues from heads of rats given the antipsychotic drug trifluoperazine (TFP). Contributions to the in vivo (19)F spectra from tissues other than brain were negligible. The in vivo (19)F resonance at -62.3 ppm from CCl(3)F consisted of 6-8 resolved resonances in vitro. Some in vitro resonances were assigned to previously identified TFP metabolites. Multiple resonances in vitro partially explain the relatively large line width seen in vivo for TFP. Unidentified metabolites were observed at about -74 to -75 ppm in a number of spectra of extracts of brain and muscle.

Effects of antipsychotic drugs on metabolite ratios in rat brain in vivo.

Localized in vivo proton magnetic resonance spectroscopy at 4.7 T was used to examine the brains of rats that were given the antipsychotic drugs haloperidol, clozapine, or olanzapine for 1 week. Spectra were collected before and during treatment. The ratios of N-acetylaspartate (NAA) to creatine (Cr) and choline to Cr were determined from the spectra. No significant differences in these ratios were seen among the rats given the various antipsychotic medications or between the control rats and the treated rats. No significant time-dependent changes were seen in most cases, except for a small reduction of NAA/Cr after 7 days of olanzapine administration. These results suggest that differences in brain metabolite ratios in vivo in schizophrenics relative to controls, at least for short-term treatment, arise from the disease, and not as a metabolic effect of the medication.

Multicenter evaluation of the MicroScan Rapid Gram-Negative Identification Type 3 Panel.

The accuracy and performance of the revised MicroScan Rapid Gram-Negative Identification Type 3 Panel (Dade MicroScan Inc., West Sacramento, Calif.) were examined in a multicenter evaluation. The revised panel database includes data for 119 taxa covering a total of 150 species, with data for 12 new species added. Testing was performed in three phases: the efficacy, challenge, and reproducibility testing phases. A total of 405 fresh and stock gram-negative isolates comprising 54 species were tested in the efficacy phase; 96.8% of these species were identified correctly in comparison to the identification obtained either with the API 20E system (bioMérieux Vitek, Hazelwood, Mo.) or by the conventional tube method. The number of correctly identified isolates in the challenge phase, including new species added to the database, was 221 of 247, or 89.5%, in comparison to the number correctly identified by the conventional tube method. A total of 465 isolates were examined for intra- and interlaboratory identification reproducibility and gave an agreement of 464 of 465, or 99.8%. The overall reproducibility of each individual identification test or substrate was 14,373 of 14,384, or 99.9%. The new Rapid Gram-Negative Identification Type 3 Panel gave accurate and highly reproducible results in this multiple-laboratory evaluation.

Identification and characterization of Serpulina pilosicoli isolates recovered from the blood of critically ill patients.

The phenotypic and genetic characteristics of spirochetes isolated from the blood of one U.S. and six French patients with severe clinical disease or impaired immunity were examined. All spirochetes were anaerobic, weakly beta-hemolytic, positive for hippurate hydrolysis, and negative for beta-glucosidase activity. Cell lengths ranged from 4 to 8 microm, and each isolate had between 8 and 12 periplasmic flagella per cell. These features were consistent with the spirochetes' being Serpulina pilosicoli, the agent of intestinal spirochetosis. All isolates were positive in a PCR assay amplifying a portion of the S. pilosicoli 16S rRNA gene, and they all grouped with fecal isolates of S. pilosicoli in multilocus enzyme electrophoresis (MLEE). The blood isolates could be differentiated from each other by MLEE, although the U.S. and two French isolates were closely related. Apparently S. pilosicoli may translocate from the large intestine to establish spirochetemia. The clinical significance of this finding remains uncertain and requires further investigation.

Did the sterile insect technique or weather eradicate screwworms (Diptera:Calliphoridae) from Libya?

The American screwworm, Cochliomyia hominivorax Coquerel, was detected in northwestern Libya in 1988. By August 1990, a screwworm epizootic extended over 26,000 km2 but collapsed in December and disappeared in April 1991. The relative contributions of winter weather and sterile insect releases on screwworm eradication in Libya were assessed by using temperature data and population demography. A screwworm overwintering threshold mean temperature of approximately 9.7 degrees C for 3 mo is supported strongly by published experimental and epizootiological data. In Libya, temperatures were above this overwintering threshold at Zawia, Sorman, and Tripoli weather stations. At Gharyan, in the interior highlands, mean winter temperatures from 1 December 1990 to 28 February 1991 were less than the putative overwintering threshold. No kill of screwworm pupae or adults was likely as a result of low temperatures near any weather station in the winter of 1990-1991. Evidence of screwworm overwintering in 1990-1991 was provided by the detection of a natural infestation in April and trap captures of numerous wild adult females in February, March, and April. Successful screwworm overwintering was highly probable in the coastal plain of Libya but unlikely in much of the interior highlands. The high rate of animal inspections by eradication personnel achieved as much as a 30% chance of detecting a screwworm case in domestic animals. Generation times and expectation of life among feral adult flies were estimated. Case reports for January to June 1991 were consistently less than estimates based on historical experience in Libya 1989-1990 and in Texas 1962-1983. Phenological simulations of sterile mating rates in feral screwworm flies supports the contention that sterile fly releases led to a greatly reduced case incidence from January to the time that eradication was declared in October 1991.

Difficulties encountered in identification of a nutritionally deficient streptococcus on the basis of its failure to revert to streptococcal morphology.

Difficulties were encountered in the recognition of a nutritionally deficient streptococcus which continued to display aberrant morphologic forms (especially bulbous swellings and filament formation) despite provision of growth factors. With isolates displaying diverse morphologic entities not characteristic of a given species, e.g., Streptobacillus moniliformis or Erysipelothrix rhusiopathiae, nutritionally deficient streptococci should be considered.

Pregnenolone sulfate potentiation of NMDA-mediated increases in intracellular calcium in cultured chick cortical neurons.

Pregnenolone sulfate (PS) has been reported to selectively augment glutamate-induced depolarizations mediated by the NMDA subtype of the glutamate receptor. The present study examines the ability of this neuroactive steroid to potentiate NMDA-mediated increases in intracellular calcium in cultured chick cortical neurons using the fluorescent dye Fura2. PS, in the absence of NMDA and glycine, significantly elevated intracellular calcium at 250 and 500 microM. This increase in free calcium was significantly attenuated at 250 microM PS by the prior addition of 50 microM CNQX, 10 microM dizocilpine or 1 microM nimodipine. NMDA and glycine, when added to the cells in saturating concentrations of 500 and 50 microM, respectively, consistently increased intracellular free calcium over baseline levels. In the presence of NMDA and glycine, both 50 and 100 microM PS produced a further significant rise in intracellular free calcium. The prior addition of CNQX, dizocilpine or both compounds together significantly inhibited this elevation in free calcium. The application of the endogenous polyamine spermine (250 microM) significantly potentiated the response of chick cortical neuronal cells to NMDA and glycine. PS, in the presence of NMDA, glycine and spermine, produced a further increase in intracellular free calcium at concentrations of 50 and 100 microM. The prior application of CNQX, dizocilpine or both compounds together significantly attenuated this rise in free calcium. These data confirm that PS is a positive allosteric modulator of the NMDA receptor and provide evidence that this neurosteroid does not interact with the polyamine modulatory site.

Isolation and characterization of the promoter of the human GABAA receptor alpha 1 subunit gene.

The GABAA receptor, as assessed by ligand binding and chloride flux measurement in vivo and in vitro, is down-regulated in response to chronic benzodiazepine exposure. The mRNA levels of the alpha 1 and gamma 2 subunits of the receptor are also reduced. We have isolated the promoter of the gene encoding the alpha 1 subunit of the GABAA receptor to elucidate the regulatory mechanism of its expression. A DNA segment 650 bp long has been isolated that includes 151 bp of untranslated 5' end of the cDNA sequence and 500 bp of potential promoter-enhancer region. The transcriptional activity of this DNA segment linked to the firefly luciferase gene showed a strong orientation specificity. The promoter activity was localized to a 60-bp segment by deletion mapping. Mobility shift binding assay results suggest that this segment may interact with one or more factors in HeLa cell nuclear extracts to form a transcriptional complex. Primary cultures of embryonic chick cortical cells transfected with the promoter-luciferase construct were treated chronically with lorazepam. Transcriptional activity of this promoter construct was strongly repressed by chronic administration of lorazepam.